1. Field of the Invention
The present invention relates to the field of ophthalmology. More particularly, the invention relates to an improved solution for maintaining the integrity, stability, and function of ocular tissues during invasive surgical procedures.
2. Discussion of Related Art
Vitreoretinal surgery, i.e., surgery involving the vitreous and retina of the posterior segment of the eye, has become commonplace as a result of the development of sophisticated surgical instrumentation and procedures. The retina is a very delicate tissue affected by a variety of diseases, such as diabetic retinopathy and cancer, as well as by physical trauma caused by accidental wounding of the eye. In an emergency vitreoretinal surgery case, the surgeon is sometimes challenged as the surgery proceeds and the extent of damage is revealed. As a result, such surgery may span a number of hours while the surgeon develops a strategy for repairing the retinal damage. This type of surgery calls for careful and deliberate decision-making and surgical precision to salvage as much viable retinal tissue, hence visual function, as possible. In any case, the surgeon wishes to avoid further damage due to the surgical procedure and manipulation of the tissue. Since the retina is exposed for some time to a potentially hostile environment as it lies open during the surgical procedure, some means for protecting retinal tissue is necessary.
When surgery of the anterior segment of the eye, usually cataract extraction with the implantation of an intraocular lens, is done, similar precautions against iatrogenic damage are routinely taken. Besides the use of careful surgical techniques, such precautions usually involve the use of a viscoelastic substance, such as sodium hyaluronate and/or chondroitin sulfate, to protect the corneal endothelium and the use of a physiological salt solution to rinse lens fragments from the eye. The anterior segment is bathed by the aqueous humor while the posterior segment contains the vitreous humor. The differences in the nature and composition of these two ocular humors relates to their respective functions and the tissues they subserve. For example, aqueous humor contains ascorbic acid which is secreted from the ciliary processes and has a consistency like that of water. On the other hand, vitreous humor has a viscous gel-like consistency. The avascular tissues of the anterior segment, i.e., the lens and cornea, depend upon the aqueous humor for nutrients and oxygen and for carrying away metabolic products. The retina receives its oxygen and nutrients from its copious vascular supply. In summary, the needs of the anterior and posterior segment tissues of the eye are similar in many respects but distinct in some.
Exdtotoxidty leads to neuronal injury due to excessive exdtatory amino acid ("EAA") stimulation. In the inner retina, glutamate is the major EAA that permits the bipolar and amacrine cells to communicate with the ganglion cell. In the central nervous system, exdtotoxidty results from hypoxia, ischemia, hypoglycemia or trauma. (See, for example, Baal, M. F., "Mechanisms of excitotoxicity in neurologic diseases," FASEB J., 6:3338-3344 (1992); and Choi, D. W., "Excitotoxic cell death," J. Neurobiol., 23:1261-1276 (1992).) Toxicity to the inner retina has been observed following intravitreal injection of EAAs following application of EAAs to the isolated animal retina or from exogenously applied glutamate to retinal ganglion cells in culture. See generally, Sattayasai, et al., "Morphology of quisqualate-induced neurotoxidty in the chicken retina," Invest. Ophthalmol. Vis. Sci., 28:106-117 (1987); Tung et al., "A quantitative analysis of the effects of excitatory neurotoxins on retinal ganglion cells in the chick," Visual Neurosci., 4:217-223 (1990); Sisk et al., "Histological changes in the inner retina of albino rats following intravitreal injection of monosodium L-glutamate," Gracfe's Arch. Clin. Exp. Ophthalmol., 223:250-258 (1985); Siliprandi et al., "N-methyl-D-aspartate-induced neurotoxicity in the adult rat retina," Visual Neurosci., 8:567-573 (1992); Reif-Lehrer et al., "Effects of monosodium glutamate on chick embryo retina in culture," Invest. Ophthalmol. Vis. Sci., 14(2):114-124 (1975); Blanks, J. C., "Effects of monosodium glutamate on the isolated retina of the chick embryo as a function of age: A morphological study," Exp. Eye Res., 32:105-124 (1981); Olney et al., "The role of specific ions in glutamate neurotoxidty," Neurosi. Lett., 65:65-71 (1986); Olney et al., "The anti-excitotoxic effects of certain anesthetics, analgesics and sedative-hypnotics," Neurosci. Lett 68:29-34 (1986); Price et al., "CNQX potently and selectively blocks kainate excitotoxicity in the chick embryo retina," Soc. Neurosci. Abst., 14:418 (1988); David et al., "Involvement of excitatory neurotransmitters in the damage produced in chick embryo retinas by anoxia and extracellular high potassium," Exp. Eye Res., 46:657-662 (1988); Caprioli et al., "Large retinal ganglion cells are more susceptible to excitotoxic and hypoxic injury than small cells," Invest. Ophthalmol. Vis. Sci,, 34(Suppl):1429 (1993); Cummins et al., "Electrophysiology of cultured refinal ganglion cells to investigate basic mechanics of damage," Glaucoma Update IV, 59-65 (1991); and Sucher et al., "N-methyl-D-aspartate antagonists prevent kainate neurotoxidty in rat retinal ganglion cells in rat retinal ganglion cells in vitro," J. Neurosci., 11(4):966-971 (1991).
EAA receptors have been characterized as metabotropic or ionotropic. Activation of a metabotropic receptor affects cellular processes via G-proteins; whereas ionotropic receptors affect the translocation of mono- and divalent cations across the cell membrane. There are at least three ionotropic receptors that have been named for the agonist that preferentially stimulates the receptor. These receptors have been classified as: N-methyl-D-aspartate (NMDA); kainate; and AMPA (2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl) propanoic acid). These EAA receptors are differentially distributed to specific cells in the retina. (See, for example, Massey, S., "Cell types using glutamate as a neurotransmitter in the vertebrate retina," N. N. Osborne and G. J. Chader (Eds.) Progress in Retinal Research, Ch. 9, Pergammon Press: Oxford, 399-425 (1990); and Miller et al., "Excitatory amino acid receptors in the vertebrate retina," in Retinal Transmitters and Modulators: Models for the Brain, (W. W. Morgan, Ed.) CRC Press, Inc., Boca Raton, II:123-160 (1985).) The localization of such receptors would account for the pathologies associated with glaucoma or inner retinal ischemia. For example, death of the retinal ganglion cell has to a large part been attributed to the NMDA receptor. (See, for example, Sucher et al., "N-methyl-D-aspartate antagonists prevent kainate neurotoxicity in retinal ganglion cells in vitro," J. Neurosci:, 11(4):966-971 (1991).) Thus, antagonists of the NMDA receptor are neuroprotective; however, not all antagonists of the diversely distributed EAA receptors are neuroprotective to the inner retina through antagonism of the NMDA receptor, Zeevalk et al., "Action of the anti-ischemic agent ifenprodil on N-methyl-D-aspartate and kainate-mediated excitotoxicity," Brain Res,, 522:135-139 (1990).
Glutamic acid is a neurotransmitter of the retina and is naturally found in that tissue. Certain cells within the retina have the ability to synthesize, release, take up and metabolize glutamic acid. It has been discovered that glutamic acid, in excessive quantity, is cytotoxic or neurotoxic to some retinal elements, notably retinal ganglion cells. Retinal ganglion cells are the cell bodies of origin for the optic nerve fibers which subserve vision. Glutamic acid is released from the retina during periods of ischemia and reperfusion, as may occur when the blood circulation is stopped and restarted in retinal blood vessels. Retinal ganglion cells, which lie close to the vitreous humor, are adversely affected by excessive glutamic acid. Glutamic acid is possibly released from retinal cells during vitreoretinal surgery if the tissue becomes anoxic or is physically traumatized. In this instance, glutamic acid could cause damage to retinal ganglion cells, and possibly other retinal cell types, unless it is prevented from interacting with its receptors located within those target cells. One means of prevention is to expose the retinal cells to an antagonist of glutamic acid during the vitreoretinal surgical procedure. Thus, bystander cells could be protected from the deleterious effects of glutamic acid and escape its toxicity. Since glutamic acid-producing cells are not known to exist in the anterior segment tissues of the eye, but are found in the retina, there is a higher probability for excessive glutamic acid damage to occur during vitreoretinal surgery compared to anterior segment surgery. This calls for the inclusion of an antagonist to glutamic acid in a physiological salt solution intended for use during vitreoretinal surgery. Even though such an antagonist may not be as useful for anterior segment surgery, it is unlikely that its presence would pose any hazard to those tissue. Thus, such a physiological salt solution could be used safely during anterior segment surgery too. The present invention is directed to satisfying the need for a physiological irrigating solution containing a glutamic acid antagonist to protect the retinal cells during vitreoretinal surgery.